title: Extracellular administration of BCL2 protein reduces apoptosis and improves survival in a murine model of sepsis.
abstract: BACKGROUND
  Severe sepsis and septic shock are major causes of morbidity and mortality worldwide. In experimental sepsis there is prominent apoptosis of various cell types, and genetic manipulation of death and survival pathways has been shown to modulate organ injury and survival.
  
  
  RESULTS
  We investigated the effect of extracellular administration of two anti-apoptotic members of the BCL2 (B-cell lymphoma 2) family of intracellular regulators of cell death in a murine model of sepsis induced by cecal ligation and puncture (CLP). We show that intraperitoneal injection of picomole range doses of recombinant human (rh) BCL2 or rhBCL2A1 protein markedly improved survival as assessed by surrogate markers of death. Treatment with rhBCL2 or rhBCL2A1 protein significantly reduced the number of apoptotic cells in the intestine and heart following CLP, and this was accompanied by increased expression of endogenous mouse BCL2 protein. Further, mice treated with rhBCL2A1 protein showed an increase in the total number of neutrophils in the peritoneum following CLP with reduced neutrophil apoptosis. Finally, although neither BCL2 nor BCL2A1 are a direct TLR2 ligand, TLR2-null mice were not protected by rhBCL2A1 protein, indicating that TLR2 signaling was required for the protective activity of extracellularly adminsitered BCL2A1 protein in vivo.
  
  
  CONCLUSIONS
  Treatment with rhBCL2A1 or rhBCL2 protein protects mice from sepsis by reducing apoptosis in multiple target tissues, demonstrating an unexpected, potent activity of extracellularly administered BCL2 BH4-domain proteins.
authors.affiliation: Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwata
authors.forename: R Angelo
authors.initials: RA
authors.lastname: de Claro
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Morgan-Stevenson
authors.forename: Joan C
authors.initials: JC
authors.lastname: Tupper
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Schwartz
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Jordan
authors.forename: Robert K
authors.initials: RK
authors.lastname: Winn
authors.forename: John M
authors.initials: JM
authors.lastname: Harlan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002432:Cecum / Q000473:pathology / Q000601:surgery; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005110:Extracellular Space / Q000187:drug effects; D006801:Humans; D008026:Ligation; D051379:Mice; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D014950:Wounds, Penetrating / Q000473:pathology
chemical_list: C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins